| Project/Area Number |
18H02683
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Kumamoto University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
細野 祥之 愛知県がんセンター(研究所), がん標的治療TR分野, ユニット長 (60820363)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2018: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
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| Keywords | 癌細胞 / カベオラ / エンドサイトーシス / ROR1 / 細胞膜 / カベオリン / 生体膜ダイナミクス / メンブレントラフィック / 細胞内輸送 / 癌 |
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| Outline of Final Research Achievements |
ROR1 is a transcriptional target of the lineage-survival oncogene TTF-1 in lung adenocarcinomas. Here, we report that ROR1 possesses a novel scaffold function indispensable for efficient caveolae-dependent endocytosis. CAVIN3 was found to bind with ROR1 at a site distinct from sites for CAV1 and CAVIN1, a novel function required for caveolae-dependent endocytosis, but not caveolae formation itself. Furthermore, evidence of a mechanistic link between ROR1-CAVIN3 interaction and consequential caveolae trafficking, which was found to utilize a binding site distinct from those for ROR1 interactions with CAV1 and CAVIN1, with RTK-mediated pro-survival signaling towards AKT in early endosomes in lung adenocarcinoma cells was also obtained. The present findings warrant future study to enable development of novel therapeutic strategies for inhibiting the multifaceted scaffold functions of ROR1 in order to reduce the intolerable death toll from this devastating cancer.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、ROR1がカベオラ形成を介した細胞膜の構造と生理機能を調節する、腫瘍生物学における新たな制御機構の解明につながる可能性があり、その一端を明らかにすることができ、学術的意義を有していると思われる。また今後の研究によっては、カベオラと呼ばれる生体膜の制御因子として重要な機能発現に関わるROR1分子の作用機序とその破綻による疾患との関連性が明らかになることで、生体膜や脂質異常に伴う多種の疾患や、がんの発生・進展等の分子機序解明とそれに基づく治療法の開発にも大きくつながり、医学領域にも大いに貢献できるものと考える。
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